Bicyclic analgesic compounds

ABSTRACT

Analgesic compounds for treatment of pain or fever, comprising a bicyclopentane moiety linked to an amine, combinations of the compounds with opioid analgesic drugs, and methods for treating pain or fever by administering the compounds.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claimis identified in the Application Data Sheet as filed with the presentapplication, are hereby incorporated by reference under 37 CFR 1.57,such as U.S. Application No. 61/781,580, filed Mar. 14, 2013.

BACKGROUND

1. Field

This disclosure relates to small molecule drugs typified by a bicyclicaliphatic group. The disclosed compounds include analgesic compounds andantipyretic compounds. Also disclosed are methods of synthesis, drugcombinations, and medical uses.

2. Description

Nonsteroidal anti-inflammatory compounds, or NSAIDs, are an extremelyuseful group of small molecule drugs, typified by acetylsalicylic acid,ibuprofen, and naproxen. These are often sold without prescription, andare variously used to treat pain, inflammation, and fever. However,NSAIDs can have undesirable side effects, including gastric upset orgastric bleeding.

Acetaminophen, also known as paracetamol or APAP, is also an effectivepain reliever often sold over the counter (without prescription).Although it shares analgesic and antipyretic properties with NSAIDs, ithas only weak anti-inflammatory properties, and is thus not an NSAID.Unlike many NSAIDs, acetaminophen does not cause gastric upset orbleeding in prescribed doses. Thus, it is an extremely useful drug forthose wishing analgesia without adverse gastric side effects.

Acetaminophen is often combined with other drugs for relief of symptomsof influenza and the common cold, among other indications. It isparticularly useful in combination with opioid analgesics, where itexhibits synergistic analgesic properties and allows patients to achieveadequate pain relief with lower doses of opioids. The most widelyprescribed drug in the United States is a combination of acetaminophenand hydrocodone, with over 130 million prescriptions in the year 2010.Other acetaminophen-opioid combinations, including combinations withoxycodone, are also widely prescribed.

Acetaminophen poisoning is the most common cause of acute liver failurein the Western world, and acetaminophen accounts for the most drugoverdoses in the English-speaking world. Acetaminophen is metabolized toform N-acetyl-p-benzoquinoneimine (NAPQI), which depletes glutathione inthe liver and injures hepatocytes, leading to acute liver failure andoften death. The acetaminophen-opioid combination drugs are commonlyimplicated in such toxicity, for various reasons. First, patients mightnot recognize that the prescribed pain relievers contain acetaminophen,and may supplement with acetaminophen if pain relief is inadequate.Second, continued administration of opioids can lead to tolerance andthe need for increased dosages to obtain a comparable opioid effect, andusers or abusers of the combination drugs may exceed safe dosages ofacetaminophen as a consequence.

This has led the U.S. FDA to seek reduced amounts of acetaminophen inthe opioid combination drugs and has also led an FDA advisory panel torecommend banning such drugs all together. Although theacetaminophen-opioid drugs remain on the market, there is a strong needfor a less toxic replacement without the same hepatotoxicity risks.

Acetaminophen has the structure:

Acetaminophen is metabolized in vivo to form the hepatotoxic compoundN-acetyl-p-benzoquinoneimine:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a synthetic pathway for creating abicyclo[1.1.1]pentyl amide compound.

FIG. 2 illustrates a synthetic pathway for creating hydroxybicyclo[1.1.1]pentyl amide compounds.

FIG. 3 illustrates a synthetic pathway for creating analgesic ethers andprodrug esters of bicyclo[1.1.1]pentyl compounds.

SUMMARY

Disclosed are compounds having analgesic properties that do not formbenzoquinoneimine metabolites and, thus, avoid the hepatotoxicitymechanism of acetaminophen. These include compounds of Formula 1:

wherein

R¹ is H, —CH₃, CF₃, or (C₂ to C₅) substituted or unsubstituted loweralkyl;

R² is H or C(═Y)R⁴;

R³ is H, F, D, hydroxy, (C₁ to C₁₀)alkoxy, (C₁ to C₃₀) substituted orunsubstituted alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, heterocycle, heteroaryl, arylalkyl, alkylaryl,heteroarylalkyl, or —(C═O)L;

R⁴ is CF₃ or (C₁ to C₁₀) substituted or unsubstituted lower alkyl;

Y is S or O; and

(C═O)L is a hydrolyzable prodrug ester leaving group.

In some embodiments, L is a substituted or unsubstituted alkyl,cycloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, heterocycle, heteroaryl, arylalkyl, alkylaryl,heteroarylalkyl, or any combination of such groups, all of which may besubstituted or unsubstituted and which may range from C₁ to C₃₀ orotherwise include from 1 to 30 atoms, excluding hydrogen.

In some embodiments, L has the structure —CH₃, CH₂CH₃, CH₂CH₂OH,

DETAILED DESCRIPTION

Embodiments of the present compounds include a core structure having abicyclo[1.1.1]pentane group. It should be noted that due to valenceconsiderations, it is impossible to connect a substituent through adouble bond (such as a carbonyl or imine group) at either end ofbicyclo[1.1.1]pentane (i.e., at the 1 or 3 positions). Thus, likelymetabolic products of the compounds disclosed herein do not includeanalogs of benzoquinoneimine, and thus do not present a hepatotoxicityrisk through the NAPQI mechanism.

Definitions:

As used herein, the term “alkyl” refers to a fully saturated aliphatichydrocarbon group. The alkyl moiety may be branched or straight chain.Examples of branched alkyl groups include, but are not limited to,isopropyl, sec-butyl, t-butyl and the like. Examples of straight chainalkyl groups include, but are not limited to, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, and the like.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused fashion. A cycloalkenyl group may be unsubstituted or substituted.

As used herein, “cycloalkynyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more triple bonds in atleast one ring. If there is more than one triple bond, the triple bondscannot form a fully delocalized pi-electron system throughout all therings. When composed of two or more rings, the rings may be joinedtogether in a fused fashion. A cycloalkynyl group may be unsubstitutedor substituted.

The term “alkoxy” used herein refers to straight or branched chain alkylradical covalently bonded to the parent molecule through an —O— linkage.Examples of alkoxy groups include, but are not limited to, methoxy,ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy andthe like.

The term “alkenyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon double bond including, but not limited to, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

The term “alkynyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon triple bond including, but not limited to, 1-propynyl, 1-butynyl,2-butynyl, and the like.

The term “aryl” used herein refers to homocyclic aromatic radicalwhether one ring or multiple fused rings. Moreover, the term “aryl”includes fused ring systems wherein at least two aryl rings, or at leastone aryl and an ortho-fused bicyclic carbocyclic radical having aboutnine to ten ring atoms in which at least one ring is aromatic share atleast one chemical bond. Examples of “aryl” rings include, but are notlimited to, optionally substituted phenyl, biphenyl, naphthalenyl,phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.

The term, “heterocycle” or “heterocycle group” used herein refers to anoptionally substituted monocyclic, bicyclic, or tricyclic ring systemcomprising at least one heteroatom in the ring system backbone. Theheteroatoms are independently selected from oxygen, sulfur, andnitrogen. The term, “heterocycle” includes multiple fused ring systems.Moreover, the term “heterocycle” includes fused ring systems that mayhave any degree of saturation provided that at least one ring in thering system is not aromatic. The monocyclic, bicyclic, or tricyclic ringsystem may be substituted or unsubstituted, and can be attached to othergroups via any available valence, preferably any available carbon ornitrogen. Preferred monocyclic ring systems are of 4, 5, 6, 7, or 8members. Six membered monocyclic rings contain from up to threeheteroatoms wherein each heteroatom is individually selected fromoxygen, sulfur, and nitrogen, and wherein when the ring is fivemembered, preferably it has one or two heteroatoms wherein eachheteroatom is individually selected from oxygen, sulfur, and nitrogen.Preferred bicyclic cyclic ring systems are of 8 to 12 members andinclude spirocycles. An example of an optional substituent includes, butis not limited to, oxo (═O).

The term “heteroaryl” used herein refers to an aromatic heterocyclicgroup, whether one ring or multiple fused rings. In fused ring systems,the one or more heteroatoms may be present in only one of the rings.Examples of heteroaryl groups include, but are not limited to,benzothiazyl, benzoxazyl, quinazolinyl, quinolinyl, isoquinolinyl,quinoxalinyl, pyridyl, pyrrolyl, oxazolyl, indolyl, thienyl, and thelike. The term “heterocycle” encompasses heteroaryl fused to anon-aromatic ring system.

The term “heteroatom” used herein refers to, for example, oxygen, sulfurand nitrogen.

The term “amino” used herein refers to a nitrogen radical substitutedwith hydrogen, alkyl, aryl, or combinations thereof. Examples of aminogroups include, but are not limited to, —NHMethyl, —NH₂, —NMethyl₂,—NPhenylMethyl, —NHPhenyl, —NEthylMethyl, and the like.

The term “arylalkyl” used herein refers to one or more aryl groupsappended to an alkyl radical. Examples of arylalkyl groups include, butare not limited to, benzyl, phenethyl, phenpropyl, phenbutyl, and thelike.

The term “heteroarylalkyl” used herein refers to one or more heteroarylgroups appended to an alkyl radical. Examples of heteroarylalkylinclude, but are not limited to, pyridylmethyl, furanylmethyl,thiopheneylethyl, and the like.

The term “aryloxy” used herein refers to an aryl radical covalentlybonded to the parent molecule through an —O— linkage.

The term “alkylthio” used herein refers to straight or branched chainalkyl radical covalently bonded to the parent molecule through an —S—linkage.

The term “carbonyl” used herein refers to C═O (i.e. carbon double bondedto oxygen).

The term “oxo” used herein refers to ═O (i.e. double bond to oxygen).For example, cyclohexane substituted with “oxo” is cyclohexanone.

The term “alkanoyl” used herein refers to a “carbonyl” substituted withan “alkyl” group, the “alkanoyl” group is covalently bonded to theparent molecule through the carbon of the “carbonyl” group. Examples ofalkanoyl groups include, but are not limited to, methanoyl, ethanoyl,propanoyl, and the like. Methanoyl is commonly known as acetyl.

As used herein, a radical indicates species with a single, unpairedelectron such that the species containing the radical can be covalentlybonded to another species. Hence, in this context, a radical is notnecessarily a free radical. Rather, a radical indicates a specificportion of a larger molecule. The term “radical” can be usedinterchangeably with the term “group.”

The term “pro-drug ester” refers to derivatives of the compoundsdisclosed herein formed by the addition of any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofpro-drug ester groups include, but are not limited to fatty acid esters,pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl,as well as other such groups known in the art, including a(5-R-2-oxo-1,3-dioxolen-4-yl)methyl group. Other examples of pro-drugester groups can be found in, for example, T. Higuchi and V. Stella, in“Pro-drugs as Novel Delivery Systems”, Vol. 14, A.C.S. Symposium Series,American Chemical Society (1975); and “Bioreversible Carriers in DrugDesign: Theory and Application”, edited by E. B. Roche, Pergamon Press:New York, 14-21 (1987) (providing examples of esters useful as prodrugsfor compounds containing carboxyl groups). Each of the above-mentionedreferences is herein incorporated by reference in their entirety.

The abbreviation (C_(n)) in conjunction with the name of a chemicalgroup (e.g., alkyl) refers to the number of carbon atoms in that group.Thus, the term (C₁-C₅) alkyl means an alkyl group having 1 to 5 carbonatoms.

As used herein, a substituted group is derived from the unsubstitutedparent structure in which there has been an exchange of one or morehydrogen atoms for another atom or group.

Asymmetric carbon atoms may be present in the compounds described. Allsuch isomers, including diastereomers and enantiomers, as well as themixtures thereof are intended to be included in the scope of the recitedcompound. In certain cases, compounds can exist in tautomeric forms. Alltautomeric forms are intended to be included in the scope. Likewise,when compounds contain an alkenyl or alkenylene group, there exists thepossibility of cis- and trans-isomeric forms of the compounds. Both cis-and trans-isomers, as well as the mixtures of cis- and trans-isomers,are contemplated. Thus, reference herein to a compound includes all ofthe aforementioned isomeric forms unless the context clearly dictatesotherwise.

Various forms are included in the embodiments, including polymorphs,solvates, hydrates, conformers, salts, and prodrug derivatives. Apolymorph is a composition having the same chemical formula, but adifferent structure. A solvate is a composition formed by solvation (thecombination of solvent molecules with molecules or ions of the solute).A hydrate is a compound formed by an incorporation of water. A conformeris a structure that is a conformational isomer. Conformational isomerismis the phenomenon of molecules with the same structural formula butdifferent conformations (conformers) of atoms about a rotating bond.Salts of compounds can be prepared by methods known to those skilled inthe art. For example, salts of compounds can be prepared by reacting theappropriate base or acid with a stoichiometric equivalent of thecompound.

The term “animal” as used herein includes birds, reptiles, and mammals(e.g. domesticated mammals and humans).

The terms “individual,” “host,” “subject,” and “patient” are usedinterchangeably herein, and refer to a mammal, including, but notlimited to, murines, simians, humans, mammalian farm animals, mammaliansport animals, and mammalian pets.

As used herein, “pharmaceutically acceptable” refers to a material thatis not biologically or otherwise undesirable, e.g., the material may beincorporated (e.g., at the time of manufacturing or administration) intoa pharmaceutical composition administered to an individual withoutcausing any significant undesirable biological effects or interacting ina deleterious manner with any of the other components of the compositionin which it is contained. As used herein, the term “pharmaceuticallyacceptable carrier,” refers to, for example, solvents, stabilizers,pH-modifiers, tonicity modifiers, adjuvants, binders, diluents, etc.,known to the skilled artisan that are suitable for administration to anindividual (e.g., a human). Combinations of two or more carriers arealso contemplated in the present invention. The pharmaceuticallyacceptable carrier(s) and any additional components, as describedherein, should be compatible for use in the intended route ofadministration (e.g., oral, parenteral) for a particular dosage form.Such suitability will be easily recognized by the skilled artisan,particularly in view of the teaching provided herein. Pharmaceuticallyacceptable carriers or excipients have preferably met the requiredstandards of toxicological and manufacturing testing and/or are includedon the Inactive Ingredient Guide prepared by the U.S. Food and Drugadministration.

The term, “effective amount,” as used herein refers to an amount thatresults in a desired pharmacological and/or physiological effect in anindividual who has or is suspected of having (e.g., based on symptomsand/or an individual's perceptions/feelings) a disease or condition orwho displays one or more of its symptoms. An effective amount maycompletely or partially prevent the occurrence or recurrence of thedisease or condition or symptom thereof and/or may be therapeutic interms of a partial or complete cure for the disease or condition and/oradverse effect attributable to the disease or condition (e.g., pain). Inreference to a disease or condition described herein (e.g., pain), aneffective amount may comprise an amount sufficient to, among otherthings, reduce and/or relieve to some extent one or more of the symptomsassociated with a disease or condition that is responsive toacetaminophen (e.g., pain, fever, inflammation, ischemic injury (such asmyocardial and/or cerebral), or neuronal injury). In certainembodiments, the effective amount is sufficient to prevent thecondition, as in being administered to an individual prophylactically.Effective amount includes the eradication or amelioration of theunderlying condition being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying conditionsuch that the individual reports an improvement in feeling or condition(e.g., decreased pain intensity and/or duration), notwithstanding thatthe individual may still be afflicted with the underlying disease orcondition. Effective amount also includes halting or slowing theprogression of the disease or condition, regardless of whetherimprovement or the disease or condition is realized.

The “effective amount” may vary depending on the composition beingadministered, the condition being treated/prevented (e.g., the type ofpain), the severity of the condition being treated or prevented, theage, body size, weight, and relative health of the individual, the routeand form of administration, the judgment of the attending medical orveterinary practitioner (if applicable), and other factors appreciatedby the skilled artisan in view of the teaching provided herein. Aneffective amount may be assessed, for example, by using data from one ormore clinical, physiological, biochemical, histological,electrophysiological, and/or behavioral evaluations.

As is understood in the art, an “effective amount” may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more additional pharmaceuticalagents, and an acetaminophen prodrug may be considered to be given in aneffective amount if, in conjunction with one or more additionalpharmaceutical agents, one or more desirable or beneficial result(s) maybe or are achieved.

When used with respect to methods of treatment and/or prevention and theuse of the compounds of Formula 1 described herein, an individual “inneed thereof” may be an individual who has been diagnosed with,previously treated for, and/or suspected of having the disease orcondition to be treated. With respect to prevention, the individual inneed thereof may also be an individual who is at risk for a disease orcondition (e.g., a family history of the condition, life-style factorsindicative of risk for the condition, etc.).

Compounds of Formula 1 will now be further described:

wherein

R¹ is H, —CH₃, CF₃, or (C₂ to C₅) substituted or unsubstituted loweralkyl;

R² is H or C(═Y)R⁴;

R³ is H, hydroxy, (C₁ to C₁₀)alkoxy, or —O(C═O)L,

R⁴ is CF₃ or (C₁ to C₁₀) substituted or unsubstituted lower alkyl;

Y is S or O; and

(C═O)L is a hydrolyzable prodrug ester leaving group.

In some embodiments, L is a substituted or unsubstituted alkyl, aryl,alkenyl, heterocycle, heteroaryl, arylalkyl, alkylaryl, heteroarylalkyl,or any combination of such groups, all of which may be substituted orunsubstituted and which may range from C₁ to C₃₀ or otherwise includefrom 1 to 30 atoms, excluding hydrogen.

In some embodiments, L has the structure —CH₃, CH₂CH₃, CH₂CH₂OH,

Particular nonlimiting embodiments of the compounds of Formula 1 includethe following:

Synthesis:

The various analgesic compounds contemplated herein can be synthesizedfrom known starting materials by various routes. Some suitable routesare illustrated in FIGS. 1-3, with syntheses described in more detail inthe following description and Examples.

The commercially available 3-aminobicyclo[1.1.1]pentane-1-carboxylicacid can be converted to the methyl ketone intermediate by treatmentwith either methyl lithium or methylmagnesium bromide (Scheme 1).Baeyer-Villagar type oxidation with mCPBA or other peroxycarboxylicacids can give 3-aminobicyclo[1.1.1]pentan-1-yl acetate. The amine canthen be coupled with an appropriate carboxylic acid or acid chloride,such as acetyl chloride to give 3-acetamidobicyclo[1.1.1]pentan-1-ylacetate (3). Selective hydrolysis of the ester group with hydroxide iongives N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1).Alternatively, starting with the commercially available3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid and carrying out aCurtius reaction or modified Curtius reaction using diphenylphosphorylazide gives the amino alcohol intermediate, which can then be treatedwith acetyl chloride (1 eq) in the presence of base (for example, K₂CO₃,Na₂CO₃, TEA, and the like) to giveN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) or with acetylchloride (>2 eq) in the presence of base (for example, K₂CO₃, Na₂CO₃,TEA, and the like) to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate(3).

The commercially available bicyclo[1.1.1]pentan-1-amine can be coupledwith an appropriate carboxylic acid or acid chloride, such as acetylchloride in the presence of base (for example, K₂CO₃, Na₂CO₃, NaHCO₃,TEA, pyridine, and the like) to giveN-(bicyclo[1.1.1]pentan-1-yl)acetamide (4) (Scheme 2).

C—H activation or oxidation reagents are described in the followingreferences, which are hereby incorporated by reference in theirentirety: H₂SO₄ (conc.)/HNO₃ (conc. or 50%) [Cao K. et al., J LabelCompd Radiopharm 2007; 50: 1224-1229; Wanka, L., et al., Eur. J. Org.Chem. 2007, 1474-1490]; H₂SO₄ (conc.)/NH₄NO₃ [Zarubaev V. V. et al.,Bioorganic & Medicinal Chemistry 18 (2010) 839-848];perfluoro-cis-2-n-butyl-3-n-propyloxaziridine [Sorochinsky A. E., etal., Tetrahedron, 1997, 53, 5995-6000; Arnone A., et al., Org. Lett.,1999, 1, 281-284]; CBr₄/H₂O/Mo(CO)₆ [Khusnutdinov, R. I., et al.,Russian Journal of Organic Chemistry, 2009, 45, 1137-1142];[(Me₃tacn)RuCl₃], CAN, AgClO₄, t-BuOH/H₂On [McNeill, E., Du Bois, J.,Chem. Sci., 2012, 3, 1810-1813]; RuCl₃-xH₂O, KBrO₃, H₂O, pyridine, CH₃CN[McNeill, E., Du Bois, J., J. Am. Chem. Soc., 2010, 132, 10202-10204];dimethyldioxirane (DMD) or methyl(trifluoromethyl)dioxirane (TFDO), withor without HBF₄ [Annese, C., et al., Org. Lett., 2009, 11, 3574-3577;Asensio, G., et al., J. Am. Chem. Soc. 1993, 115, 1250-7253]; CrO₃,H₅IO₆ [Lee, S., Fuchs, P. L., J. Am. Chem. Soc. 2002, 124, 13978-13979];KMnO₄, KOH [Jasys, V. J., et al., J. Am. Chem. Soc., 2000, 122,466-473]; H₂SO₄ (conc.), (CF₃CO)₂O [Shmailov, A., et al., Tetrahedron,2010, 66, 3058-3064; Shmailov, A., et al., Tetrahedron, 2012, 68,4765-4772]; NaNO₂, TFA, O₂ [Onomura, O., et al., Synlett, 2006,2415-2418]; CrO₃, CH₃CO₂H, (H₃CO)₂O [Linz, T., Schäfer, H. J.,Tetrahedron Letters, 1987, 28, 6581-6582]; RuCl₃ (cat.), TFA, DCM,peracetic acid [Komiya, N., et al., Chem. Commun., 2001, 65-66]; DDQ,TfOH [Tanemura, K., et al., J. Chem. Soc., Perkin Trans. 1, 2001,3230-3231].

The C—H activation/oxidation (Scheme 3) of commercially availablebicyclo[1.1.1]pentan-1-amine by an appropriate oxidizing reagent orcondition (for example, H₂SO₄ (conc.)/HNO₃ (conc. or 50%); H₂SO₄(conc.)/NH₄NO₃; perfluoro-cis-2-n-butyl-3-n-propyloxaziridine;CBr₄/H₂O/Mo(CO)₆; [(Me₃tacn)RuCl₃], CAN, AgClO₄, t-BuOH/H₂O; RuCl₃-xH₂O,KBrO₃, H₂O, pyridine, CH₃CN; dimethyldioxirane (DMD) ormethyl(trifluoromethyl)dioxirane (TFDO), with or without HBF₄; CrO₃,H₅IO₆; KMnO₄, KOH; and the like) can give3-aminobicyclo[1.1.1]pentan-1-ol. The amino alcohol intermediate canthen be coupled with an appropriate carboxylic acid or acid chloride,such as acetyl chloride to give 3-acetamidobicyclo[1.1.1]pentan-1-ylacetate (3). Selective hydrolysis of the ester group with hydroxide iongives N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1).Alternatively, starting with N-(bicyclo[1.1.1]pentan-1-yl)acetamide (4),C—H activation/oxidation with an appropriate oxidizing reagent orconditions (for example, see listed above, and H₂SO₄ (conc.), (CF₃CO)₂O;NaNO₂, TFA, O₂; CrO₃, CH₃CO₂H, (H₃CO)₂O; RuCl₃ (cat.), TFA, DCM,peracetic acid; DDQ, TfOH; and the like) can giveN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1).

The treatment of N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1)with ethyl iodide in the presence of a base (such as NaHCO₃, Na₂CO₃,TEA, pyridine, NaH, and the like) givesN-(3-ethoxybicyclo[1.1.1]pentan-1-yl)acetamide (2) (Scheme 4).

Hydrolysis of N-(3-ethoxybicyclo[1.1.1]pentan-1-yl)acetamide (2) withsodium hydroxide (or basic aqueous conditions) gives3-ethoxybicyclo[1.1.1]pentan-1-amine (6) (Scheme 5).

The treatment of 3-aminobicyclo[1.1.1]pentan-1-yl acetate (prepared asdepicted in Scheme 1) with methyl iodide in the presence of base leadsto 3-(methylamino)bicyclo[1.1.1]pentan-1-yl acetate, followed byhydrolysis with aqueous hydroxide gives3-(methylamino)bicyclo[1.1.1]pentan-1-ol (Scheme 6). The amino alcoholintermediate can be coupled with an appropriate carboxylic acid or acidchloride, such as acetyl chloride in the presence of base (for example,K₂CO₃, Na₂CO₃, NaHCO₃, TEA, pyridine, NaH, and the like) to giveN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-N-methylacetamide (5).

The treatment of 3-aminobicyclo[1.1.1]pentan-1-ol with trifluoroaceticanhydride in the presence of base (for example, K₂CO₃, Na₂CO₃, NaHCO₃,TEA, pyridine, and the like) gives2,2,2-trifluoro-N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (7)(Scheme 7).

The treatment of N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1)with O-acetylsalicyloyl chloride in the presence of a base (for example,K₂CO₃, Na₂CO₃, NaHCO₃, TEA, pyridine, and the like) gives3-acetamidobicyclo[1.1.1]pentan-1-yl 2-acetoxybenzoate (8) (Scheme 8).Alternatively, the coupling ofN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) withO-acetylsalicylic acid in the presence of a coupling agents (forexample, HATU, EDCI, HOBt, HOAt, CDI, DCC, TP₃, isobutyl chloroformate,and the like) gives 3-acetamidobicyclo[1.1.1]pentan-1-yl2-acetoxybenzoate (8). Additionally, the treatment ofN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) with2-(4-isobutylphenyl)propanoyl chloride in the presence of a base (forexample, K₂CO₃, Na₂CO₃, NaHCO₃, TEA, pyridine, and the like) gives3-acetamidobicyclo[1.1.1]pentan-1-yl 2-(4-isobutylphenyl)propanoate (9)(Scheme 8). Alternatively, the coupling ofN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) with(±)-2-(4-isobutylphenyl)propanoic acid in the presence of a couplingagents (for example, HATU, EDCI, HOBt, HOAt, CDI, DCC, TP₃, isobutylchloroformate, and the like) gives 3-acetamidobicyclo[1.1.1]pentan-1-yl2-(4-isobutylphenyl)propanoate (9).

Formulation and Administration:

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including but not limited to hydrochloride, sulfate,nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

In certain aspects a prodrug form of the agent or compound may beadministered to an individual in need thereof. A “prodrug” refers to anagent that is converted into the parent drug in vivo. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent drug. They may, for instance, be bioavailable by oraladministration whereas the parent is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.An example, without limitation, of a prodrug would be a compound whichis administered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in Design ofProdrugs, (ed. H. Bundgaard, Elsevier, 1985), which is herebyincorporated herein by reference in its entirety.

The compounds of Formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Useful dosages of the compounds of Formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Such comparison can be done against an established analgesicdrug, such as acetaminophen. For example, if a particular compound ofFormula 1 is half as active as acetaminophen, then a dosage ofapproximately twice the established acetaminophen dosage may beappropriate. Conversely, if the compound of Formula 1 is twice as activeas acetaminophen, then a dosage of half the established acetaminophendosage can be used.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will often be in the range of fromabout 0.15 to about 100 mg/kg, e.g., from about 1 to about 75 mg/kg ofbody weight per day, such as 0.75 to about 50 mg per kilogram bodyweight of the recipient per day, preferably in the range of 1 to 90mg/kg/day, most preferably in the range of 1 to 60 mg/kg/day.

The compound is conveniently administered in unit dosage form; forexample, containing 1 to 2000 mg, conveniently 10 to 1000 mg, mostconveniently, 5 to 500 mg of active ingredient per unit dosage form.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

Combination Drug

The various compounds of Formula 1 can be administered alone or incombination with other drugs. A particularly preferred combination is acompound of Formula 1 in combination with an opioid analgesic. Any ofthe known opioid analgesics can be combined with a compound ofFormula 1. As nonlimiting examples, such analgesics include morphine,codeine, hydrocodone, oxycodone, and hydromorphone.

By way of example, an orally available dosage form of a combination ofan opioid drug with a compound of Formula 1 may include from about 20 toabout 1000 mg of a compound of Formula 1 in a unit dosage form that alsoincludes one of the following exemplary opioids: 1-20 mg hydrocodone(such as hydrocodone bitartrate), preferably 2.5 mg, 5 mg, 7.5 mg or 10mg of hydrocodone or salt thereof; or 1-20 mg oxycodone, preferably 2.5mg, 5 mg, 7.5 mg or 10 mg of hydrocodone or salt thereof (such as thehydrochloride salt).

Other combinations include combination of a compound of Formula 1 withbutalbital, codeine, dihydrocodeine, ibuprofen, aspirin, or naproxen.Administration of any of the combination drugs can be done using thesame routes and protocols as described above for compounds of Formula 1.

Methods of Treatment:

The compounds of Formula 1 can be used alone or in any of the foregoingcombinations with opioids or other drugs to treat a disease or condition(other than inflammation) that is responsive to an NSAID or anycondition responsive to acetaminophen (e.g., pain and/or fever). In oneembodiment, the invention provides a method of treating such a diseaseor condition comprising administering to an individual an effectiveamount of a compound of Formula 1 alone or as a combination. In someembodiments, the individual is at risk of developing a disease orcondition that is responsive to acetaminophen. In some embodiments,methods of treating pain, fever, inflammation, ischemic injury (such asmyocardial and/or cerebral), or neuronal injury in an individual,comprising administering to the individual an effective amount of acompound of Formula 1 or combination thereof are provided. In onevariation, the individual is post-operative and has or is believed tohave or has actually developed post-operative pain. In one variation,the drug or drug combination is administered prophylactically forpost-operative pain.

Some embodiments embrace methods of treating pain of any etiology,including acute and chronic pain, and any pain in which acetaminophenanalgesic is prescribed. Examples of pain include post-surgical pain,post-operative pain (including dental pain), migraine, headache andtrigeminal neuralgia, pain associated with burn, wound or kidney stone,pain associated with trauma (including traumatic head injury),neuropathic pain (e.g., peripheral neuropathy and post-herpeticneuralgia), pain associated with musculo-skeletal disorders, strains,sprains, contusions, fractures, such as myalgia, rheumatoid arthritis,osteoarthritis, cystitis, pancreatitis, inflammatory bowel disease,ankylosing spondylitis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism and peri-articular disorders, and painassociated with cancer (including “break-through pain” and painassociated with terminal cancer). Examples of pain with an inflammatorycomponent (in addition to some of those described above) includerheumatic pain, pain associated with mucositis, and dysmenorrhea. Insome variations, the methods and formulations of the present inventionare used for treatment or prevention of post-surgical pain and/or cancerpain. In some variations, the methods and compositions of the presentinvention are used for treatment or prevention of pain that is selectedfrom the group consisting of pain associated with surgery, trauma,osteoarthritis, rheumatoid arthritis, lower back pain, fibromyalgia,postherpetic neuralgia, diabetic neuropathy, HIV-associated neuropathyand complex regional pain syndrome.

In some variations, the compounds of Formula 1 are used alone or incombination for treatment or prevention of pain and/or fever (e.g., inadults, children and/or infants). In some embodiments, they are used fortreatment of pain, such as acute pain (e.g., acute pain followingsurgery, such as orthopedic surgery of adults, children, and/orinfants). In some embodiments, they are used for treatment or preventionof fever, such as endotoxin-induced fever (e.g., endotoxin-induced feverin adults, children, and/or infants). In some embodiments, they are usedfor treatment or prevention of fever in children and/or infants. In someembodiments, the fever is selected from low-grade fever, moderate fever,high-grade fever and hyperpyrexia fever. In some embodiments, the feveris selected from Pel-Ebstein fever, continuous fever, intermittentfever, and remittent fever.

In some embodiments, the methods include delaying the onset of analgesiain an individual in need thereof, wherein the method comprisesadministering to the individual an effective amount of a prodrug ofFormula 1 that (in comparison to the parent drug) delays drug action bygreater than about 5 minutes, or 10 minutes, or 15 minutes, or 30minutes, or 1 hour, or 2, hours, or 3 hours, or 4 hours, or 6 hours, or8 hours, or 10 hours, or 12 hours, or 18 hours, or 24 hours.

In any of the foregoing methods, administration by injection or infusionrepresents a preferred technique, and intravenous administration overthe course of 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2hours, 6 hours, 12 hours, 24 hours or longer, or any intermediate time,is particularly preferred. Such administration can, in somecircumstances, substitute for or significantly reduce the need foradministration of opiates, and is of significant benefit in painmanagement in hospitals or other care facilities. One particular methodcomprises intravenous administration to an individual in need thereof tomanage post-operative or other acute or chronic pain, in either a bolusdose or by infusion over minutes, hours, or days.

Another method is a selecting a therapy for managing or treating pain inan individual in need thereof, comprising evaluating whether theindividual is at risk for hepatic toxicity from pain therapy, andselecting therapy with a compound of Formula 1 to reduce or eliminatesuch risk. The method can further include administering the selectedtherapy with a compound of Formula 1 to the individual.

Yet another method is a method for providing combination pain therapy.Combinations of a compound of Formula 1 and an opioid analgesic cansynergistically relieve pain. The can result in reduction in opioid use.Thus, the method may include managing, treating, or reducing pain byadministering an effective amount of a combination of a compound ofFormula 1 and an opioid analgesic to a patient. A related method is amethod for reducing opioid use in pain management, by selecting and/oradministering an amount of a compound of Formula 1 in combination withan amount of an opioid analgesic, wherein the combination providessignificantly more pain relief than the amount of either compound alone.

The disclosure can be further understood with reference to the followingnonlimiting Examples.

EXAMPLE 1 Preparation ofN-(3-hydroxybicyclo[1.1.1]-pentan-1-yl)acetamide (1)

Step 1. To a solution of 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid(1 mmol) in anhydrous THF (2 mL) at 0° C. under nitrogen is added amethyllithium (1.4 M in diethyl ether, 4 mmol) in a dropwise manner.After addition, the reaction mixture is slowly allowed to warm to roomtemperature, stirred overnight, and treated with aqueous saturatedammonium chloride solution (4 mL). Ethyl acetate (2 mL) is added andorganic layer are separated. The aqueous layer is extracted with ethylacetate (3×1 mL). The combined organic layers are dried (Mg₂SO₄) andconcentrated. The residue is purified by a flash chromatography onsilica gel (EtOAc/hexnaes) to give1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethanone.

Step 2. A solution of 1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethanone (1mmol) in 0.5 mL of chloroform is added to a stirred mixture ofm-chloroperbenzoic acid (1.5 mmol) in 2 mL of chloroform at roomtemperature. The solution is stirred in the dark for 24 h. The mixtureis filtered, and the filtrate is washed with 10% sodium bicarbonate andthen water. The organic layer is dried over magnesium sulfate andconcentrated. The residue is purified by a flash chromatography onsilica gel (EtOAc/hexnaes) to give 3-aminobicyclo[1.1.1]pentan-1-ylacetate.

Step 3: To a DMF (2 mL) solution of 3-aminobicyclo[1.1.1]pentan-1-ylacetate (1 mmol) is added sodium bicarbonate (3 mmol) and then acetylchloride (1 mmol) by syringe at 0° C. The reaction is allowed to warm upto room temperature and monitored by LCMS. After LCMS analysis indicatedconsumption of starting material, the reaction is diluted with water andextracted with EtOAc (3×). The organic layers are combined, washed withbrine, dried (magnesium sulfate), filtered, and concentrated. The cruderesidue is subjected to flash chromatography (silica gel, EtOAc/hexanes)to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3).

Step 4: To a THF (2 mL) solution of 3-acetamidobicyclo[1.1.1]pentan-1-ylacetate (3) (1 mmol) is added methanol (0.7 mL) followed by a aqueoussolution of NaOH (1.4 M, 0.7 mL, 1 eq) at room temperature. The mixtureis stirred and monitored by TLC. After complete consumption of thestarting material, saturated ammonium chloride is added and the mixtureis stirred for 5 min. The volatiles are removed under vacuum and theresultant mixture is extracted with EtOAc (3×). The organic layers arecombined, dried (magnesium sulfate), filtered, and concentrated. Thecrude residue is subjected to flash chromatography (silica gel,EtOAc/hexanes) to give N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide(1).

EXAMPLE 2 Preparation of N-(3-ethoxybicyclo[1.1.1]-pentan-1-yl)acetamide(2)

To a anhydrous THF (5 mL) solution ofN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) (1 mmol) is addedNaH (60% dispersion in mineral oil, 3 mmol) portionwise at 0° C. Afteraddition, the mixture is stirred until the evolution of gas stops.Iodoethane (1 mmol) is then added by syringe slowly. The reaction ismonitored by LCMS and TLC. After consumption of starting material, thereaction mixture is quenched by adding water (3 mL) and extracted withethyl acetate (3×). The organic layers are combined, dried (magnesiumsulfate), filtered, and concentrated. The crude residue is subjected toflash chromatography (silica gel, EtOAc/hexanes) to affordN-(3-ethoxybicyclo[1.1.1]pentan-1-yl)acetamide (2).

EXAMPLE 3 Preparation of 3-acetamidobicyclo[1.1.1]-pentan-1-yl acetate(3)

The general procedure of Example 1 is repeated to Step 3, to produce3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3).

EXAMPLE 4 Preparation of N-(bicyclo[1.1.1]-pentan-1-yl)acetamide (4)

To a DMF (12.62 mL) solution of bicyclo[1.1.1]pentan-1-amine, HCl (604mg, 5.05 mmol) was added sodium bicarbonate (1.272 g, 15.14 mmol) andthen acetyl chloride (0.359 mL, 5.05 mmol) by syringe at 0° C. Thereaction was allowed to warm up to room temperature and monitored byLCMS. After LCMS analysis indicated consumption of starting material,the reaction was diluted with water and extracted with EtOAc (3×). Theorganic layers were combined, washed with brine and then dried(magnesium sulfate), filtered, and concentrated. The crude residue wassubjected to flash chromatography (silica gel, 0-100% EtOAc/hexanes) togive N-(bicyclo[1.1.1]pentan-1-yl)acetamide (4), as a white solid.MH+=126.2. ¹H NMR (CDCl₃) ppm: 1.91 (s, 3H), 2.06 (s, 6H), 2.42 (s, 1H),5.88 (br s, 1H).

EXAMPLE 5 Preparation ofN-(3-hydroxybicyclo[1.1.1]-pentan-1-yl)-N-methylacetamide (5)

Step 1: To an anhydrous DMF (5 mL) solution of3-aminobicyclo[1.1.1]pentan-1-yl acetate (1 mmol; prepared as describedin Example 1, Step 2) is potassium carbonate (3 mmol) followed by theaddition of methyl iodide (1 mmol) by syringe at room temperature. Thereaction is monitored by LCMS and TLC. After consumption of startingmaterial, the reaction mixture is quenched by adding water (3 mL) andextracted with ethyl acetate (3×). The organic layers are combined,dried (magnesium sulfate), filtered, and concentrated. The crude residueis subjected to flash chromatography (silica gel, EtOAc/hexanes) toafford 3-(methylamino)bicyclo[1.1.1]pentan-1-yl acetate.

Step 2: To a THF (2 mL) solution of 3-acetamidobicyclo[1.1.1]pentan-1-ylacetate (3) (1 mmol) is added methanol (0.7 mL) followed by a aqueoussolution of NaOH (4 M, 0.7 mL, 3 eq) at room temperature. The mixture isstirred and monitored by TLC. After complete consumption of the startingmaterial, saturated ammonium chloride (3 mL) is added and the mixture isstirred for 5 min. The volatiles are removed under vacuum and theresultant mixture is extracted with EtOAc (3×). The organic layers arecombined, dried (magnesium sulfate), filtered, and concentrated. Thecrude residue is subjected to flash chromatography (silica gel,EtOAc/hexanes) to give 3-(methylamino)bicyclo[1.1.1]pentan-1-ol.

Step 3: The general procedure of Example 1 Step 3 is repeated startingwith 3-(methylamino)bicyclo[1.1.1]pentan-1-ol to produceN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-N-methylacetamide (5).

EXAMPLE 6 Preparation of 3-ethoxybicyclo[1.1.1]-pentan-1-amine (6)

The general procedure of Example 5 Step 2 is repeated starting withN-(3-ethoxybicyclo[1.1.1]pentan-1-yl)acetamide (2) to produce3-ethoxybicyclo[1.1.1]pentan-1-amine (6).

EXAMPLE 7 Preparation of2,2,2-trifluoro-N-(3-hydroxybicyclo[1.1.1]-pentan-1-yl)acetamide (7)

The general procedure of Example 1 Step 3 is repeated starting with3-(methylamino)bicyclo[1.1.1]pentan-1-ol and using trifluoroaceticanhydride in place of the acetyl chloride to produce2,2,2-trifluoro-N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (7).

EXAMPLE 8 Preparation of 3-acetamidobicyclo[1.1.1]-pentan-1-yl2-acetoxybenzoate

The general procedure of Example 1 Step 3 is repeated starting withN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) and usingO-acetylsalicyloyl chloride in place of the acetyl chloride to produce3-acetamidobicyclo[1.1.1]pentan-1-yl 2-acetoxybenzoate (8).

EXAMPLE 9 Preparation of 3-acetamidobicyclo[1.1.1]-pentan-1-yl2-(4-isobutylphenyl)propanoate (9)

The general procedure of Example 1 Step 3 is repeated starting withN-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) and using2-(4-isobutylphenyl)propanoyl chloride in place of the acetyl chlorideto produce 3-acetamidobicyclo[1.1.1]pentan-1-yl2-(4-isobutylphenyl)propanoate (9).

What is claimed is:
 1. A compound of Formula 1:

wherein R¹ is H, —CH₃, CF₃, or a substituted or unsubstituted (C₂ to C₅)lower alkyl; R² is C(═Y)R⁴; R³ is F, D, hydroxy, (C₁ to C₁₀) alkoxy, (C₁to C₃₀) substituted or unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, or —(C═O)L; R⁴ is CF₃ or (C₁ toC₁₀) substituted or unsubstituted lower alkyl; Y is S or O; and —(C═O)Lis a hydrolyzable prodrug ester leaving group.
 2. The compound of claim1, wherein L is a substituted or unsubstituted alkyl, cycloalkyl, aryl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle,heteroaryl, arylalkyl, alkylaryl, heteroarylalkyl, or any combination ofsuch groups, all of which may be substituted or unsubstituted and whichmay range from C₁ to C₃₀ or otherwise include from 1 to 30 atoms,excluding hydrogen.
 3. The compound of claim 1, wherein L is —CH₃,CH₂CH₃, CH₂CH₂OH,


4. The compound of claim 1, having one of the following structures:


5. A method for treating an individual, comprising identifying anindividual in need of treatment to reduce or at least partially preventpain or fever; and administering to the individual an effective amountof a compound of claim
 1. 6. A method for treating an individual,comprising identifying an individual in need of treatment to reduce orat least partially prevent pain or fever; and administering an effectiveamount of an opioid analgesic in conjunction with administering to theindividual the compound of Formula 1:

wherein R¹ is H, —CH₃, CF₃, or a substituted or unsubstituted (C₂ to C₅)lower alkyl; R² is H or C(═Y)R⁴; R³ is F, D, hydroxy, (C₁ to C₁₀)alkoxy, (C₁ to C₃₀) substituted or unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, or —(C═O)L; R⁴ is CF₃or (C₁ to C₁₀) substituted or unsubstituted lower alkyl; Y is S or O;and —(C═O)L is hydrolyzable prodrug ester leaving group.
 7. The methodof claim 5, wherein the administration is intravenous.
 8. The method ofclaim 7, wherein the pain is post-operative pain.